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Polymer-sunitinib conjugates

Active Publication Date: 2013-12-12
NEKTAR THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent describes a new compound that contains a sunitinib residue attached to a water-soluble, non-peptidic polymer through a releasable linkage-containing spacer moiety. This compound and its pharmaceutically acceptable salts have various technical effects, including improved solubility, reduced toxicity, and improved stability. The patent also provides methods for making and using the compound. Overall, this invention provides a new way to improve the performance of sunitinib as a therapeutic agent.

Problems solved by technology

Both of PDGR-Rs and VEGFRs play a role in tumor proliferation and angiogenesis, and sunitinib's ability to inhibit these targets leads to cancer cell death and reduced tumor vascularization, thereby resulting in tumor shrinkage.
Treatment with sunitinib, however, is not without drawbacks, including hand-foot syndrome, stomatitis, and other toxicities.

Method used

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Examples

Experimental program
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Effect test

example 1

Synthesis of Amino-Diethyleneglycol Linked PEG-Sunitinib Conjugates

[0205]This example references one or more of the following compounds.

Synthesis of (Z)-2-(diethylamino)ethyl(5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carbonyl)carbamic chloride (Compound 1)

[0206]In a 500 mL round-bottomed flask was suspended sunitinib (2.0 g, 5.1 mmol) in THF (200 mL). To this yellow suspension was added triethylamine (11.8 mL, 84 mmol). The suspension was heated in an oil bath with stirring at 60° C. for several minutes to give an orange solution. The solution was cooled for several minutes before transfer to the triphosgene reaction.

[0207](Caution: To prevent release of toxic phosgene gas from either the reaction apparatus or rotary evaporator, the equipment setups were sparged through a sodium hydroxide scrub solution via an over pressure or exhaust port.) In a separate 1 L round-bottomed flask was added triphosgene (1.6 g, 5.4 mmol) in THF (40 mL) to give a colorless s...

example 2

Synthesis of Amino-Propanol Linked PEG-Sunitinib Conjugates

[0222]

Synthesis of (Z)-(tert-butyl 3-hydroxypropylcarbamate) 2-(diethylamino)ethyl(5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carbonyl)carbamate (Compound 1b)

[0223]Synthesis was conducted as described in Method A substituting tert-butyl 3-hydroxypropylcarbamate (Compound b) (0.83 mL, 4.8 mmol) to give a orange suspension. Product precipitation in phosphate buffer and extraction were omitted. Purified product yield was 41 mg of yellow powder. HPLC analysis was on a C18 silica column applying an acetonitrile gradient with 0.1% TFA; retention times observed were sunitinib 3.7 minutes and product 9.1 minutes with 99% purity at 370 nm. Analysis by LC-MS ([C31H43FN5O6]+ expected M+H=600.32. found M+H=600.3). 1H-NHR (d6-DMSO): δ (ppm) 0.9 (6H, bm, CH3); 1.3 (9H, s, CH3); 1.5 (2H, m, CH2); 2.3 (3H, s, CH3); 2.4 (3H, s, CH3); 2.6 (2H, bm, CH2); 2.8 (2H, m, CH2); 3.8 (2H, bs, CH2); 4.0 (2H, t, CH2); 6.8 (1H,...

example 3

Synthesis of Hydroxyethylpiperazine Linked PEG-Sunitinib Conjugates

[0227]

Synthesis of (Z)-(tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate) 2-(diethylamino)ethyl(5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carbonyl)carbamate (Compound 1c)

[0228]Synthesis was conducted as described in Method A substituting tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (Compound c) (3.8 g, 17 mmol) in anhydrous tetrahydrofuran (12 mL) and anhydrous acetonitrile (8 mL) to give a orange suspension. Purified product yield was 0.2 g of yellow powder. HPLC analysis was on a C18 silica column applying an acetonitrile gradient with 0.1% TFA; retention times observed were sunitinib 3.4 minutes and product 4.7 minutes with 99% purity at 370 nm. Analysis by LC-MS ([C34H48FN6O6]+ expected M+H=655.36. found M+H=655.3). 1H-NHR (CDCl3): δ (ppm) 1.0 (6H, t, CH3); 1.4 (9H, s, CH3); 2.3 (4H, m, CH2); 2.4 (3H, s, CH3); 2.5 (3H, s, CH3); 2.6 (4H, m, CH2); 2.8 (2H, m, CH2); 3.3 (4H,...

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Abstract

The invention relates to (among other things) polymer-sunitinib conjugates and related compounds. A compound of the invention, when administered by any of a number of administration routes, exhibits advantages over sunitinib in unconjugated form.

Description

CROSS REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application Ser. No. 61 / 426,919, filed on Dec. 23, 2010, the disclosure of which is incorporated herein by reference.FIELD OF THE INVENTION[0002]This invention comprises (among other things) chemically modified forms of the receptor tyrosine kinase (RTK) inhibitor, sunitinib, which forms possess certain advantages over sunitinib lacking the chemical modification. The chemically modified forms of sunitinib described herein relate to and / or have application(s) in (among others) the fields of drug discovery, pharmacotherapy, physiology, organic chemistry and polymer chemistry.BACKGROUND OF THE INVENTION[0003]Protein kinases (“PKs”) are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues within proteins. Phosphorylation of these hydroxy groups is required for the growth, differentiation and proli...

Claims

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Application Information

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IPC IPC(8): A61K47/48
CPCA61K47/48215A61K31/404A61K47/60A61P35/00A61P43/00A61K47/58
Inventor CULBERTSON, SEAN M.KOZLOWSKI, ANTONIVINSON, TONY DREW
Owner NEKTAR THERAPEUTICS INC
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